Antilipidemic para-[aryl(alkyl or alkenyl)amino]-benzoic acid derivatives

ABSTRACT

Novel para-[aryl(alkyl or alkenyl)amino]benzoic acids, esters, pharmaceutically acceptable salts and pharmaceutical compositions thereof and a method of lowering serum lipid levels in mammals therewith.

BACKGROUND OF THE INVENTION

Considerable effort has been directed in recent years toward obtainingsubstances which are useful in the treatment of hyperlipidemia, acondition associated with elevated serum lipid levels, e.g., elevatedcholesterol, phospholipid and/or triglyceride serum levels. Thiscondition is associated with a number of diseases, one of the mostserious being atherosclerosis. Medicaments used to lower cholesterol,phospholipid and triglyceride serum levels are termed hypolipidemic orantilipidemic drugs. Presently three major lipid-lowering agents areavailable: clofibrate, D-thyroxine, and nicotinic acid. [R. I. Levy andD. S. Fredrickson, Post-graduate Medicine, Vol. 47, pps. 130-136(1970).] The class of lipid lowering compounds encompassed by thepresent invention may be referred to as para-[aryl(alkyl oralkenyl)amino]benzoic acid derivatives.

U.S. Pat. No. 3,716,644 discloses and claims a method of lowering serumlipid levels in mammals by the administration of certain meta and paraalkoxybenzoic acids, esters, pharmaceutically acceptable salts andpharmaceutical compositions thereof. U.S. Pat. No. 3,868,416 disclosesand claims certain 4-(monoalkylamino)benzoic acids, esters,pharmaceutically acceptable salts, pharmaceutical compositions thereofand a method of lowering serum lipid levels in mammals therewith. GermanPat. No. 716,668 discloses the compound p-[(3-phenylpropyl)amino]benzoicacid, however, no utility other than that in a chemical process is givenfor the compound. The compound p-benzylaminobenzoic acid is disclosed inChemical Abstracts 42:5033b, 43:1345i, 54:2487e, 48:649b, 48:32846c and49:10886g; ethyl p-benzylaminobenzoate in Chemical Abstracts 38:P2346²,51:8720 g and J. Org. Chem. 26:1437 (1961);p-[(p-methoxybenzyl)amino]benzoic acid in J. Chem. Soc. 1088 (1970);ethyl p-(β-phenethylamino)benzoate and p-(β-phenethylamino)benzoic acidin Chemical Abstracts 40:559³ ; and the compoundp-[β-(3,4-dimethoxyphenyl)ethylamino]benzoic acid in Chemical Abstracts54:13154 g. No prior art is known which discloses the para-[aryl(alkylor alkenyl)amino]benzoic acid derivatives of this invention and/or theirutility as antilipidemic agents.

SUMMARY OF THE INVENTION

This invention is concerned with and contemplates as novel antilipidemiccompounds those compounds which may be referred to as para-[aryl(alkylor alkenyl)amino]benzoic acid derivatives and which may be representedby the formula: ##STR1## wherein R₁ is selected from the group hydrogen,lower alkyl, benzyl, diloweralkylaminoethyl and loweralkoxyethyl; R₂ isselected from the group aryl and substituted aryl; A is selected fromthe group C_(n) H_(2n), wherein n=1-16 (with the proviso that when n=1or 2, R₂ must not be phenyl, monomethoxy- or dimethoxyphenyl and whenn=3 and R₁ =H, R₂ must be substituted aryl) and C_(n) H_(2n) --₂,wherein n=3-14 16; the pharmaceutically acceptable acid addition saltsthereof; and when R₁ =H, the alkali metal or organic base carboxylicacid salts thereof.

Suitable lower alkyl groups contemplated by this invention are thosehaving 1-6 carbon atoms, as, for example, methyl, ethyl, isopropyl,propyl, tert-amyl and n-hexyl. Suitable lower alkenyl groupscontemplated are allyl, 1, 2 or 3-butenyl, and pentenyl. Suitable C_(n)H_(2n) and C_(n) H_(2n) --₂ groups are both branched and straight chain.Suitable aryl and substituted aryl groups include, for example, phenyl,substituted phenyl such as 4-halophenyl, 2,4-dihalophenyl,2,4,6-trihalophenyl, 4-lower alkoxyphenyl, 2,4-di-loweralkoxyphenyl,2,4,6-tri-loweralkoxyphenyl, 4-benzyloxyphenyl, 4-loweralkylphenyl,2,4-di-loweralkylphenyl, 2,4,6-tri-loweralkylphenyl, 1-naphthyl,2-naphthyl, 2-furoyl, 2-thienyl and biphenyl.

As a method of lowering serum lipid levels in mammals, this inventioncontemplates and comprises orally administering to said mammals aneffective lipid-lowering amount of a para-[aryl(alkyl oralkenyl)amino]benzoic acid derivative of the formula: ##STR2## whereinR₁ is selected from the group hydrogen, lower alkyl, benzyl,diloweralkylaminoethyl and loweralkoxyethyl; R₂ is selected from thegroup aryl and substituted aryl; A is selected from the group C_(n) H₂n, wherein n=1-16 and C_(n) H_(2n) --₂, wherein n=3-16; thepharmaceutically acceptable salts thereof; and when R₁ =H, the alkalimetal or organic base carboxylic acid salts thereof.

This invention also contemplates a therapeutic composition in unitdosage form which is useful to lower serum lipid levels in mammalscomprising a para-[aryl(alkyl or alkenyl)amino]benzoic acid derivativeof the formula: ##STR3## wherein R₁ is selected from the group hydrogen,lower alkyl, benzyl, diloweralkylaminoethyl and loweralkoxyethyl; R₂ isselected from the group aryl and substituted aryl; A is selected fromthe group C_(n) H_(2n), wherein n=1-16 and C_(n) H_(2n) --₂, whereinn=3-16; the pharmaceutically acceptable salts thereof; and when R₁ =H,the alkali metal or organic base carboxylic acid salts thereof, inconcentration per dosage unit to provide a daily dosage of from about 35mg. to about 2.8 g., preferably from about 140 mg. to about 2.0 g.; anda pharmaceutical carrier.

DETAILED DESCRIPTION OF THE INVENTION

The novel para-[aryl(alkyl or alkenyl)amino]benzoic acid derivatives ofthe present invention are in general colorless or tan crystalline solidswith some being colorless or tan oils. The compounds are soluble inorganic solvents such as benzene, chloroform, dichloromethane,N,N-dimethylformamide, dimethylsulfoxide and lower alkanols. They arebases and may be converted to their non-toxic addition salts with acidssuch as sulfuric, hydrochloric, phosphoric, succinic, citric and thelike. The compounds wherein R₁ is hydrogen may be reacted with alkalibases such as sodium hydroxide and potassium hydroxide or with organicbases such as ammonium hydroxide, pyridine, mono-, di-, or tri-loweralkylamines such as methylamine, diethylamine, trimethylamine,dibutylamine and the like to obtain the corresponding carboxylic acidsalts.

The novel para-[aryl(alkyl or alkenyl)amino]benzoic acid derivatives ofthis invention are prepared by reacting lower alkyl p-aminobenzoateswith alkylating agents such as arylalkyl or arylalkenyl halides,arylalkanol or arylalkenol O-sulfates, O-tosylates,O-trifloromethylsulfonates, O-methanesulfonates with or without solventat 50° C. to 150° C. Suitable solvents are hexamethylphosphoramide,N,N-dimethylformamide, N,N-dimethylacetamide, lower alkanols,chloroform, dimethylsulfoxide, benzene, xylene, acetonitrile and thelike. The reaction may be carried out with an equivalent of base such asan alkali carbonate or bicarbonate.

Alternatively, the arylalkyl or arylalkenyl aminobenzoates may beprepared by reaction of a lower alkyl p-aminobenzoate with an arylalkylor arylalkenyl halide, in the presence of an equivalent of sodiumhydride in an inert solvent such as hexamethylphosphoramide,N,N-dimethylformamide, N,N-dimethylacetamide and xylene at 50° C. to150° C. In the case or arylalkyl or arylalkenyl chlorides the alkylationof lower alkyl p-aminobenzoates may be carried out in an inert solventsuch as hexamethylphosphoramide, N,N-dimethylformamide andN,N-dimethylacetamide with an equivalent of dry sodium iodide orpotassium iodide to promote the reaction.

The p-arylalkyl and p-arylalkenyl aminobenzoic acids are prepared byhydrolysis of the corresponding benzoate esters by reacting with analkali metal hydroxide such as sodium or potassium hydroxide in a loweralkanol, water or an aqueous lower alkanol at 25° C. to 100° C.Alternatively, the acids may be prepared by hydrolysis of the loweralkyl benzoates with mineral acids such as hydrochloric, hydrobromic,sulfuric, in water or aqueous lower alkanols.

Esters of p-arylalkyl- and p-arylalkenyl aminobenzoic acids may beprepared by conversion of the appropriate acid to an acid chloride withreagents such as thionyl chloride and oxalyl chloride and then reactingthe intermediate acid chloride with lower alkanols, diloweralkylaminoethanol, lower alkoxyethanol and the like.

Alternatively, the novel arylalkylaminobenzoates may be prepared byreductive alkylation of a lower alkyl p-aminobenzoate or p-aminobenzoicacid with a suitable arylalkyl-aldehyde or ketone in the presence ofnoble metals and (or) nickel or cobalt catalysts or a suitable metalhydride. For example, Raney nickel hydrogen and an arylalkylaldehyde maybe used to reductively alkylate ethyl p-aminobenzoate. Auxiliarycatalysts such as aluminum chloride, piperidine acetate or acids may beused in the reductive alkylation. Similarly, arylalkenylaminobenzoatesmay be prepared by reductive alkylation of a suitablearylalkenylaldehyde or ketone in the presence of noble metals and (or)nickel or cobalt catalyst or a suitable metal hydride.

EXAMPLE 1 Preparation of p-(Phenethylamino)benzoic acid

A mixture of 16.5 g. of ethyl p-aminobenzoate, 10.3 g. of(2-bromoethyl)benzene and 50 ml. of hexamethylphosphoramide is heated inan oil bath at 115°-120° C. for 17 hours. The mixture is put into iceand water and extracted with ether. The ether extracts are washed withwater, dried over magnesium sulfate and concentrated in vacuo to an oil.The oil is combined with 200 ml. of ethanol-water (9:1) and 20 g. ofpotassium hydroxide and the mixture is refluxed for 3.5 hours. Afterchilling the mixture is made acidic with concentrated hydrochloric acid,diluted with 150 ml. of water, chilled, diluted with water and extractedwith chloroform. The chloroform extracts are washed with water, driedover magnesium sulfate and concentrated in vacuo to a gum. Ethanol isadded, the mixture is chilled and filtered to give yellow crystals. Themother liquors are chilled at -20° C. to give a second crop of crystals.Recrystallization of the combined crops of crystals from hexane-ethanolgives yellow crystals, m.p. 123°- 125° C. Recrystallization from ethanolgives pale yellow crystals, m.p. 124°-126° C.

EXAMPLE 2 Preparation of p-(Decyloxy)benzyl alcohol

To 100 ml. of 1.0 M borane in tetrahydrofuran cooled in an ice bathunder nitrogen is added dropwise, 27.8 g. of p-decyloxybenzoic acid in300 ml. of tetrahydrofuran over a period of 45 minutes. The mixture isstirred at room temperature for 6 hours and poured onto ice, dilutedwith water and 10 ml. of concentrated hydrochloric acid. The mixture isfiltered and the solid washed with water to give white crystals.Recrystallization from ethanol gives white plates, m.p. 57.5°-59° C.

EXAMPLE 3 Preparation of p-(Decyloxy)benzyl alcohol o-methanesulfonate

A mixture of 15.9 g. of p-(decyloxy)benzyl alcohol (prepared asdescribed in Example 2) and 9.1 ml. of triethylamine in 300 ml. ofdichloromethane is chilled to -15° C. in an ice-salt bath. To thesolution is added dropwise 5.1 ml. of methanesulfonyl chloride in 5 ml.of dichloromethane over a period of 10 minutes. The mixture is stirredat -15° C. for 30 minutes and at -8° C. for 10 minutes. The mixture iswashed with 100 ml. of ice cold water, 100 ml. of cold 10% hydrochloricacid, 100 ml. of cold saturated sodium bicarbonate and with 100 ml. ofcold saturated sodium chloride solution. The organic layer is dried overmagnesium sulfate and the solvent removed in vacuo. The residue isdissolved in dichloromethane and extracted with saturated sodiumbicarbonate solution. The organic layer is dried over magnesium sulfateand concentrated in vacuo to give a pale yellow oil.

EXAMPLE 4 Preparation of p-{[p-(Decyloxy)benzyl]amino}benzoic acid

A mixture of 16.5 g. of ethyl p-aminobenzoate, 15.6 g. ofp-(decyloxy)benzyl alcohol O-methanesulfonate (prepared as described inExample 3) and 50 ml. of hexamethylphosphoramide is heated at 120° C.for 22 hours. The solution is cooled, diluted with 10 ml. of water and50 ml. of ethanol and chilled. Filtration gives a solid which is washedwith 50 ml. of ethanol and with water. A second crop is obtained fromthe filtrate. The two crops of gummy solid are heated with ethanol andthe solvent decanted until 200 ml. of extract is obtained (some oilyinsoluble solid remains). The ethanol extracts are chilled, filtered andthe solid washed once with ethanol to give tan crystals.Recrystallization from ethanol gives off-white crystals.

The solid is combined with 50 ml. of ethanol, 10 ml. of water and 6 g.of potassium hydroxide and the mixture refluxed for 4 hours. The mixtureis diluted with 10 ml. of water, acidified with concentratedhydrochloric acid, diluted with water and chilled. Filtration gives asolid which is washed with water, dried and washed with benzene (50 ml.)to give crystals, m.p. 130°-135° C. and 158°-160° C. Recrystallizationfrom ethanol and from acetone gives white crystals, m.p. 131°-134° C.and 159°-161° C.

EXAMPLE 5 Preparation of Ethyl p-[(4-biphenylmethyl)amino]benzoate andp-[(4-Biphenylmethyl)amino]benzoic acid

A mixture of 16.5 g. of ethyl p-aminobenzoate, 10.1 g. of4-chloromethylbiphenyl and 50 ml. of hexamethylphosphoramide are heatedat 120° C. for 22 hours. The mixture is chilled, diluted with 18 ml. ofwater, chilled and filtered. The solid is washed with water and withethanol to give tan crystals. Recrystallization from a mixture of 300ml. of ethanol and 75 ml. of benzene gives tan crystals, m.p. 165°-168°C. Recrystallization from acetone gives tan crystals, m.p. 164°-167° C.

A mixture of 5 g. of the above ethyl ester, 5 g. of potassium hydroxideand 100 ml. of ethanol-water (9:1) is refluxed for 3 hours. The mixtureis acidified with concentrated hydrochloric acid, diluted with 25 ml. ofwater, chilled and filtered to give pale yellow crystals, m.p. 231°-235°C. Recrystallization from ethanol-benzene gives yellow crystals, m.p.234°-237° C.

EXAMPLE 6 Preparation of 11-Phenyl-1-undecanol

To 200 ml. of 1M borane in tetrahydrofuran, cooled in an ice bath undernitrogen, is added dropwise over 35 minutes, a solution of 52.5 g. ofphenylundecanoic acid in 150 ml. of tetrahydrofuran. The solution isallowed to stand at room temperature for 5.5 hours and poured onto ice.To the mixture is added 8 ml. of concentrated hydrochloric acid and themixture is diluted with water to 2.2 liters. The mixture is extractedwith ether (ca 500 ml.) and the extracts dried over magnesium sulfate.Concentration in vacuo gives a colorless oil.

EXAMPLE 7 Preparation of 11-Phenyl-1-undecanol O-methanesulfonate

To a mixture of 750 ml. of dichloromethane, 37.2 g. of11-phenyl-1-undecanol (prepared as described in Example 6) and 32 ml. oftriethylamine cooled in an ice-salt bath to -10° C. is added dropwise,over 15 minutes, 13.2 ml. of methanesulfonyl chloride. The mixture iscooled at -10° C. to -15° C. for 30 minutes and then washed with 300 ml.of cold water, 300 ml. of cold 10% hydrochloric acid, 300 ml. of cold 5%sodium carbonate and with 200 ml. of cold, saturated, sodium chloridesolution. The organic layer is dried over magnesium sulfate andconcentrated in vacuo to give a pale yellow oil.

EXAMPLE 8 Preparation of p-[(11-Phenylundecyl)amino]benzoic Acid

A mixture of 16.5 g. of ethyl p-aminobenzoate, 16.3 g. of11-phenylundecanol O-methanesulfonate (prepared as described in Example7) and 50 ml. of hexamethylphosphoramide are heated in an oil bath at120° C. for 20 hours. The mixture is poured into ice and water andextracted with chloroform. The extracts are washed with water, 0.1 NNaOH, saturated sodium chloride solution and water. After drying overmagnesium sulfate the extract is filtered through silica gel and thesilica gel is washed with chloroform. The filtrate is concentrated invacuo to an oil which is combined with 200 ml. of ethanol-water (9:1),15 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours.The mixture is acidified with concentrated hydrochloric acid, dilutedwith 50 ml. of water and chilled. Dilution with 100 ml. of ethanol and25 ml. of water and filtration gives a gummy solid which is washed withwater. The solid is dissolved in hexane:ether:ethyl acetate:acetic acid(40:5:5:2) and filtered through silica gel G. The support is washed withthe same solvent (2 fractions). The first fraction is concentrated invacuo to an oil which is crystallized from hexane to give pale yellowcrystals, m.p. 50°-52° C. Recrystallization from ether-hexane (1:1)gives white crystals, m.p. 53°-55° C.

EXAMPLE 9 Preparation of Ethyl p-benzylaminobenzoate

A mixture of 16.5 g. of ethyl p-aminobenzoate, 8.55 g. of benzyl bromideand 45 ml. of hexamethylphosphorimide are heated in an oil bath at 110°C. for 20 hours. The mixture is diluted with water, chilled, filteredand the solid washed with water to give tan crystals, m.p. 90°-93° C. Asample is recrystallized from ethanol to give tan crystals, m.p. 96°-97°C.

EXAMPLE 10 Preparation of p-Benzylaminobenzoic Acid

A mixture of 6.0 g. of ethyl p-benzylaminobenzoate (prepared asdescribed in Example 9), 100 ml. of ethanol-water (9:1) and 6.0 g. ofpotassium hydroxide are refluxed for 3.5 hours. The mixture is acidifiedwith concentrated hydrochloric acid, diluted with water, chilled,filtered and the solid washed with water to give pale cream crystals,m.p. 165°-168° C. Recrystallization from ethanol gives tan crystals,m.p. 167°-169° C.

EXAMPLE 11 Preparation of Ethyl p-[p-(benzyloxy)benzylamino]benzoate

A mixture of 16.5 g. of ethyl p-aminobenzoate, 11.64 g. ofp-benzyloxybenzyl chloride and 50 ml. of hexamethylphosphoramide areheated in an oil bath at 110° C. for 20 hours. The mixture is chilled,diluted with 25 ml. of water, chilled and the solid mass diluted withadditional water in order to filter. The solid is washed with water andrecrystallized from ethanol to give off-white crystals, m.p. 144°-146°C. A sample is recrystallized from ethanol to give off-white crystals,m.p. 146°-147° C.

EXAMPLE 12 Preparation of p-[p-(Benzyloxy)benzylamino]benzoic Acid

A mixture of 10 g. of ethyl p-[p-(benzyloxy)benzylamino]benzoate(prepared as described in Example 11) 10 g. of potassium hydroxide and200 ml. of ethanol-water (9:1) are refluxed for 4.5 hours. While hot,the mixture is acidified with concentrated hydrochloric acid. Dilutionwith water and filtration gives tan crystals which are recrystallizedfrom glacial acetic acid to give off-white crystals, m.p. 206°-208° C.

EXAMPLE 13 Preparation of p-[6-(Phenylhexyl)amino]benzoic Acid

A solution of 8.13 g. of ethyl p-[6-(phenylhexyl)amino]benzoate and 2.81g. of potassium hydroxide in 90 ml. of 95% ethnol is heated at refluxfor 5 hours. Five ml. of concentrated HCl is added to the hot reactionmixture. The mixture is cooled to room temperature, 100 ml. of water isadded and the mixture is refrigerated. The product is collected byfiltration, washed with water, dried and then recrystallized fromabsolute ethanol yielding tan needles, m.p. 126°-129° C.

EXAMPLE 14 Preparation of Ethyl p-[(p-Methoxybenzyl)amino]benzoate

A mixture of 33 g. of ethyl p-aminobenzoate, 100 ml. ofhexamethylphosphoramide and 15.7 g. of p-(chloromethyl)anisole areheated at 100°-110° C. for 22 hours. The solution is chilled, dilutedwith 60 ml. of water, chilled, filtered and the solid washed withethanol and with water to give yellow crystals. Recrystallization fromethanol gives pale yellow crystals, m.p. 128°-130° C.

EXAMPLE 15 Preparation of p-[(p-Methoxybenzyl)amino]benzoic Acid

A mixture of 15 g. of ethyl p-[(p-methoxybenzyl)amino]benzoate,(prepared as described in Example 14) 15 g. of potassium hydroxide and200 ml. of ethanol-water (9:1) are refluxed for 3 hours, acidified whilehot with concentrated hydrochloric acid, diluted with water, cooled,filtered and the solid is washed with water to give tan crystals, m.p.208°-210° C. Recrystallization from ethanol gives off-white crystals,m.p. 209°-210° C.

EXAMPLE 16 Preparation of p-(Benzyloxy)phenethanol

To 120 ml. of 1.0 M borane in tetrahydrofuran cooled in an ice bath isadded dropwise 14.5 g. of (p-benzyloxyphenyl)acetic acid in 100 ml. ofdry tetrahydrofuran over a period of 25 minutes. After 17 hours at roomtemperature the mixture is poured onto ice. After the ice meltsfiltration gives white crystals, m.p. 72°-75° C.

EXAMPLE 17 Preparation of p-(Benzyloxy)phenethanol O-methanesulfonate

To a mixture of 250 ml. of dichloromethane, 11.42 g. ofp-(benzyloxy)phenethanol (prepared as described in Example 16) and 10.7ml. of triethylamine chilled to -10° C. is added dropwise over 10minutes 6.23 g. (4.21 ml.) of methanesulfonyl chloride in 10 ml. ofdichloromethane. After 45 minutes the mixture is washed with 100 ml. ofice cold water, 100 ml. of 10% hydrochloric acid, 100 ml. of coldsaturated sodium bicarbonate solution, 100 ml. of saturated sodiumchloride, dried over magnesium sulfate and the solvent removed in vacuo.The oil crystallizes to give white crystals, m.p. 62°-65° C.

EXAMPLE 18 Preparation of Ethyl p-[(p-Benzyloxyphenethyl)amino]benzoate

A mixture of 16.5 g. of ethyl p-aminobenzoate, 15.3 g. ofp-(benzyloxy)phenethanol O-methanesulfonate (prepared as described inExample 17) and 50 ml. of hexamethylphosphoramide is heated in an oilbath at 110° C. for 20 hours. The solution is chilled, diluted with 30ml. of water, 10 ml. of ethanol, chilled, filtered and the solid iswashed with aqueous ethanol and with water. The solid is recrystallized(twice) from ethanol to give tan crystals, m.p. 94°-97° C.Recrystallization from ethanol gives tan crystals, m.p. 95°-97° C.

EXAMPLE 19 Preparation of p-[(p-Benzyloxyphenethyl)amino]benzoic Acid

A mixture of 6.0 g. of ethyl p-[(p-benzyloxyphenethyl)amino]benzoate(prepared as described in Example 18) 6.0 g. of potassium hydroxide and100 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The mixture isacidified while hot with concentrated hydrochloric acid, diluted withwater, filtered and the solid washed with water to give tan crystals,m.p. 180°-185° C. Recrystallization from glacial acetic acid gives tancrystals, m.p. 187°-189° C.

EXAMPLE 20 Preparation of p-Tridecyloxybenzyl Alcohol

To 200 ml. of 1.0 M borane in tetrahydrofuran, chilled in an ice bath isadded dropwise over 30 minutes 32.0 g. of p-tridecyloxybenzoic acid in450 ml. of tetrahydrofuran. After 22 hours at room temperature, themixture is poured onto ice. After the ice melts, the solid is filteredand washed with water to give white crystals, m.p. 72°-75° C.Recrystallization from ethanol gives white crystals, m.p. 74°-75° C.

EXAMPLE 21 Preparation of p-(Tridecyloxy)benzyl alcoholO-methanesulfonate

To a mixture of 19.1 g. of p-(tridecyloxy)benzyl alcohol (prepared asdescribed in Example 20), 9.1 ml. (6.51 g.) of triethylamine and 300 ml.of dichloromethane chilled to -10° C. is added dropwise over 10 minutes,7.5 g. (5.1 ml.) of methanesulfonyl chloride in 5 ml. ofdichloromethane. After stirring at -10° C. to -15° C. for one hour, themixture is washed with 100 ml. of ice-cold water, 100 ml. of cold 10%HCl, 100 ml. of cold saturated sodium bicarbonate, 100 ml. of coldsaturated sodium chloride solution and with 100 ml. of cold saturatedsodium bicarbonate solution. The organic layer is dried over magnesiumsulfate and concentrated to give a waxy solid.

EXAMPLE 22 Preparation of Ethyl p-[(p-tridecyloxybenzyl)amino]benzoate

A mixture of 16.5 g. of ethyl p-aminobenzoate, 19.1 g. ofp-(tridecyloxy)benzyl alcohol O-methanesulfonate (prepared as describedin Example 21) and 50 ml. of hexamethylphosphoramide is heated at 110°C. for 20 hours. The solution is chilled, diluted with 100 ml. ofethanol-water (1:1) chilled, filtered and the solid washed withethanol-water (1:1), water and ethanol. The solid is recrystallized fromethanol-benzene (7:3) to give white crystals, m.p. 95°-105° C.Recrystallization from ethanol-benzene (9:1) gives white crystals, m.p.100°-105° C.

EXAMPLE 23 Preparation of p-[(p-Tridecyloxybenzyl)amino]benzoic Acid

A mixture of 7.0 g. of ethyl p-[(p-tridecyloxybenzyl)amino]benzoate(prepared as described in Example 22), 7.0 g. of potassium hydroxide and150 ml. of ethanol-water (9:1) is refluxed for 3.5 hours. The solutionis acidified while hot, diluted with water, filtered and the solidwashed with water to give white crystals, m.p. 110°-113° C. and145°-150° C. The solid is heated with 200 ml. of glacial acetic acid andthe solution chilled and filtered to give crystals, m.p. 110°-112° C.and 155°-160° C. The filtrate is diluted with water to give whitecrystals (pure by TLC) m.p. 108°-122° C. and 150°-155° C. The first cropof crystals is slurried in 75 ml. of acetone, filtered and the filtratechilled and filtered. The filtrate is diluted with water to give whitecrystals (pure by TLC). The two crops pure by TLC are combined, dried invacuo to give white crystals, m.p. 110°-112° C. and 155°-160° C.

EXAMPLE 24 Preparation of Ethyl p-[(Cinnamyl)amino]benzoate

A mixture of 33 g. of ethyl p-aminobenzoate 15.3 g. of(3-chloropropenyl)benzene and 80 ml. of hexamethylphosphoramide isheated in an oil bath at 110° C. for 21 hours. The solution is chilled,diluted with 25 ml. of water, chilled, filtered and the solid washedwith water to give cream crystals, m.p. 123°-131° C. Recrystallizationfrom ethanol-benzene (9:1) gives pale yellow crystals, m.p. 135°-137° C.Recrystallization from benzene gives white crystals, m.p. 135°-137° C.

EXAMPLE 25 Preparation of p-(Cinnamylamino)benzoic Acid

A mixture of 10 g. of ethyl p-(cinnamylamino)benzoate (prepared asdescribed in Example 24), 10 g. of potassium hydroxide and 200 ml. ofethanol-water (9:1) is refluxed for 3 hours. The solution is acidifiedwhile hot with concentrated hydrochloric acid, diluted with water,cooled and filtered to give off-white crystals. Recrystallization fromethanol gives pale yellow crystals, m.p. 200°-202° C.

EXAMPLE 26 Preparation of Ethyl p-[(3-phenylpropyl)amino]benzoate

A mixture of 33 g. of ethyl p-aminobenzoate, 19.9 g. of(3-bromopropyl)benzene and 80 ml. of hexamethylphosphoramide is heatedat 110° C. for 20 hours. The mixture is chilled, diluted with 25 ml. ofwater, chilled, diluted with 50 ml. of ethanol and filtered. The solidis washed with cold ethanol-water (1:1) to give tan crystals, m.p.80°-83° C. Two recrystallizations from ethanol give tan crystals, m.p.87°-89° C.

EXAMPLE 27 Preparation of p-[(3-Phenylpropyl)amino]benzoic Acid

A mixture of 10 g. of ethyl p-[(3-phenylpropyl)amino]benzoate (preparedas described in Example 26), 10 g. of KOH and 200 ml. of ethanol-water(9:1) is refluxed for 4 hours. The mixture is acidified while hot withconcentrated hydrochloric acid, diluted with water, cooled and filteredto give off-white crystals. Recrystallization from ethanol givesoff-white crystals, m.p. 162°-163° C.

EXAMPLE 28 Preparation of Ethyl p-[10-phenyldecyl)amino]benzoate

A mixture of 13.2 g. of ethyl p-aminobenzoate, 10.1 g. of 10-phenyldecylchloride, 6.0 g. of sodium iodide and 50 ml. of hexamethylphosphoramideis stirred and heated in an oil bath at 110° C. for 22 hours. Themixture is chilled, diluted with 25 ml. of water, 25 ml. of ethanol,chilled and filtered. The solid is washed with water and with two 50 ml.portions of ethanol to give tan crystals, m.p. 70°-73° C.Recrystallization from ethanol gives tan crystals, m.p. 74°-76° C.

EXAMPLE 29 Preparation of p-[(10-Phenyldecyl)amino]benzoic Acid

A mixture of 7.0 g. of ethyl p-[(10-phenyldecyl)amino]benzoate (preparedas described in Example 28), 7 g. of potassium hydroxide and 100 ml. ofethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidifiedwhile hot with concentrated hydrochloric acid, diluted with water,cooled and filtered to give white crystals, m.p. 80°-87° C.Recrystallization from ethanol gives white crystals, m.p. 96°-98° C.

EXAMPLE 30 Preparation of Ethyl p-[(5-phenylpentyl)amino]benzoate

A mixture of 18.2 g. of ethyl p-aminobenzoate 10.2 g. of sodium iodide,10.0 g. of 5-phenylpentyl chloride and 60 ml. of hexamethylphosphoramideis stirred and heated at 110° C. in an oil bath for 20 hours. Themixture is chilled, diluted with 25 ml. of water and 25 ml. of ethanol,chilled and filtered. The solid is washed with 50 ml. of ethanol-water(1:1), with water and once with cold ethanol to give pale yellowcrystals, m.p. 63°-64° C. Recrystallization from ethanol gives off-whitecrystals, m.p. 73°-75° C.

EXAMPLE 31 Preparation of p-[(5-Phenylpentyl)amino]benzoic Acid

A mixture of 7 g. of ethyl p-[(5-phenylpentyl)amino]benzoate (preparedas described in Example 46), 7 g. of potassium hydroxide and 100 ml. ofethanol-water (9:1) is refluxed for 3 hours. The mixture is acidifiedwith concentrated hydrochloric acid while hot, diluted with water,cooled and filtered. The solid is washed with water to give whitecrystals, m.p. 141°-143° C. Recrystallization from ethanol gives whitecrystals, m.p. 142°-144° C.

EXAMPLE 32 Preparation of Ethyl p-[(8-Phenyloctyl)amino]benzoate

A mixture of 14.9 g. of ethyl p-aminobenzoate, 50 ml. ofhexamethylphosphoramide, 10.1 g. of 8-phenyloctyl chloride and 6.75 g.of sodium iodide is stirred and heated in an oil bath at 110° C. for 24hours. The mixture is chilled, diluted with 50 ml. of water and 25 ml.of ethanol, chilled and filtered. The solid is washed with ethanol-water(1:1) and with water to give crystals, m.p. 61°-68° C. Recrystallizationfrom ethanol gives white crystals, m.p. 75°-76° C.

EXAMPLE 33 Preparation of p-[(8-Phenyloctyl)amino]benzoic Acid

A mixture of 7 g. of ethyl p-[(8-phenyloctyl)amino]benzoate (prepared asdescribed in Example 32), 7 g. of potassium hydroxide and 100 ml. ofethanol-water (9:1) is refluxed for 3.5 hours. The mixture is acidifiedwhile hot with concentrated hydrochloric acid, diluted with water,chilled and filtered. The solid is washed with water to give off-whitecrystals, m.p. 113°-115° C. Recrystallization from ethanol gives whitecrystals, m.p. 113°-115° C.

EXAMPLE 34 Preparation of Ethyl p-[(7-Phenylheptyl)amino]benzoate

A mixture of 8.25 g. of ethyl p-aminobenzoate, 5.06 g. of7-phenylheptylchloride, 3.6 g. of sodium iodide and 25 ml. ofhexamethylphosphoramide is heated in an oil bath at 110° C. for 20hours. The mixture is chilled, diluted with 30 ml. of ethanol-water(1:1) and with water to give crystals, m.p. 65°-67° C. Recrystallizationfrom ethanol gives white crystals, m.p. 66.5°-68° C.

EXAMPLE 35 Preparation of p-[(7-Phenylheptyl)amino]benzoic Acid

A mixture of 5 g. of ethyl p-[(7-phenylheptyl)amino]benzoate (preparedas described in Example 34), 5 g. of KOH and 50 ml. of ethanol-water(9:1) is refluxed for 3.5 hours. The mixture is acidified while hot withconcentrated hydrochloric acid, diluted with H₂ O, chilled and filtered.The solid is washed with H₂ O to give off-white crystals, m.p. 123°-126°C. Recrystallization from ethanol gives tan crystals, m.p. 123.5°-125°C.

EXAMPLE 36 Preparation of p-[(9-Phenylnonyl)amino]benzoic Acid

A mixture of 13.9 g. of ethyl p-aminobenzoate, 10 g. of 9-phenylnonylchloride, 6.3 g. of sodium iodide and 50 ml. of hexamethylphosphoramideis heated at 110° C. for 20 hours. The mixture is chilled, diluted with25 ml. of ethanol-water (1:1) and with water to give off-white crystals,m.p. 62°-65° C.

The solid is combined with 1.7 g. of potassium hydroxide, 25 ml. ofethanol-water (9:1) and the mixture refluxed for 3.5 hours. The mixtureis acidified while hot with concentrated hydrochloric acid, diluted withwater, filtered and the solid washed with water to give off-whitecrystals, m.p. 105°-107° C.

EXAMPLE 37 Preparation of 4-(2-Thienyl)butanol

To 240 ml. of 1 M borane in tetrahydrofuran chilled in an ice bath, isadded dropwise, 20.4 g. of 4-(2-thienyl)butyric acid in 50 ml. oftetrahydrofuran. After the addition, the mixture is allowed to stand atroom temperature for 17 hours and is poured onto ice. After standing,the mixture is extracted with ether, the ether extract washed withwater, dried over magnesium sulfate and concentrated in vacuo to give apale yellow oil.

EXAMPLE 38 Preparation of Ethyl p-[4-(2-Thienylbutyl)amino]benzoate

To a solution of 15.6 g. of 4-(2-thienyl)butanol and 20.9 ml. (15.2 g.)of triethylamine in 500 ml. of dichloromethane, cooled to -8° C. isadded 8.45 ml. (12.5 g.) of methanesulfonyl chloride dropwise over 10minutes. The mixture is stirred at -8° C. for 25 minutes, washed with400 ml. of ice water, 200 ml. of cold 10% HCl, 200 ml. of cold saturatedsodium bicarbonate and 200 ml. of cold saturated sodium chloridesolution. The organic layer is dried over magnesium sulfate andconcentrated in vacuo to an oil. This oil is combined with 33 g. ofethyl p-aminobenzoate and 80 ml. of hexamethylphosphoramide and themixture heated in an oil bath at 105°-110° C. for 19 hours. The solutionis chilled, diluted with 35 ml. of water, chilled, 20 ml. of ethanol isadded and the mixture is filtered. The solid is washed withethanol-water (1:1) and with water and the damp solid recrystallizedfrom 150 ml. of ethanol to give tan crystals, m.p. 63°-65° C.Recrystallization from ethanol gives tan crystals, m.p. 65°-67° C.

EXAMPLE 39 Preparation of p-[4-(2-Thienylbutyl)amino]benzoic Acid

A mixture of 7.5 g. of ethyl p-[4-(2-thienylbutyl)amino]benzoate(prepared as described in Example 38), 7.5 g. of potassium hydroxide and150 ml. of ethanol-water (9:1) is refluxed for 4 hours. The mixture isacidified while hot with concentrated hydrochloric acid, diluted withwater, cooled and filtered. The solid is washed with water to give tancrystals, m.p. 137°-140° C. Recrystallization from ethanol gives tancrystals, m.p. 139°-141° C.

EXAMPLE 40 Preparation of p-[(p-Fluorophenethyl)amino]benzoic Acid

A mixture of 15.8 g. of 1-(2-chloroethyl)-4-fluorobenzene, 33 g. ofethyl p-aminobenzoate, 16.6 g. of potassium iodide and 100 ml. ofhexamethylphosphoramide is heated at 95° C. for 15 hours. The mixture ispoured into water and extracted with ether. The ether extracts arewashed with water, dried over magnesium sulfate and concentrated invacuo to an oil. To the oil is added 200 ml. of ethanol-water (9:1) and21 g. of potassium hydroxide and the mixture is refluxed for 3.5 hours.The mixture is acidified with concentrated hydrochloric acid, dilutedwith water, cooled and filtered to give gray crystals. Recrystallizationfrom ethanol gives light gray crystals, m.p. 161°-163° C.

EXAMPLE 41 Preparation of Ethylp-[3-(o-methoxyphenyl)propyl]aminobenzoate

A mixture of 14.5 g. of ethyl p-aminobenzoate, 10 g. of1-bromo-3-(o-methoxyphenyl)propane and 50 ml. of hexamethylphosphoramideis heated at 130° C. for 15 hours, cooled and diluted with 20 ml. ofwater. The mixture is chilled, diluted with 50 ml. of cold ethanol:H₂ O(1:1) and filtered. The solid is washed with three 50 ml. portions ofcold ethanol-water (1:1) and with water to give crystals, m.p. 106°-109°C. Recrystallization from ethanol (100 ml.) gives yellow crystals, m.p.111°-113° C.

EXAMPLE 42 Preparation of p-[3-(o-Methoxyphenyl)propyl]aminobenzoic Acid

A mixture of 7.0 g. of ethyl p-[3-(o-methoxyphenyl)propyl]aminobenzoate(prepared as described in Example 41), 7.0 g. of potassium hydroxide and100 ml. of ethanol-water (9:1) is refluxed for 3.5 hours, acidifiedwhile hot with concentrated hydrochloric acid, diluted with water andchilled. The mixture is filtered and the solid washed with water to giveoff-white crystals, m.p. 155°-157° C. Recrystallization from ethanolgives off-white crystals, m.p. 156°-158° C.

EXAMPLE 43 Preparation of 3-[p-(Benzyloxy)phenyl]propanolO-Methanesulfonate

To a solution of 11.0 g. of 3-[p-(benzyloxy)phenyl]propanol and 10.4 ml.of triethylamine in 175 ml. of dichloromethane chilled to -10° C. isadded dropwise, over 10 minutes, a solution of 3.89 ml. ofmethanesulfonyl chloride in 10 ml. of dichloromethane. The solution isstirred at -10° C. for 30 minutes, washed with 150 ml. of cold water, 75ml. of cold 10% HCl, 75 ml. of cold saturated sodium bicarbonate, 75 ml.of cold saturated sodium chloride solution and dried over magnesiumsulfate. The solvent is removed in vacuo to give off-white crystals,m.p. 65°-69° C.

EXAMPLE 44 Preparation of Ethylp-{{3-[p-(Benzyloxy)phenyl]propyl}amino}benzoate

A mixture of 12.8 g. of 3-[p-(benzyloxy)phenyl]propanolO-methanesulfonate (prepared as described in Example 43), 50 ml. ofhexamethylphosphoramide and 16.5 g. of ethyl p-aminobenzoate is heatedat 100°-105° C. for 17.5 hours. The mixture is chilled, diluted with 15ml. of water, 30 ml. of ethanol and chilled. In order to filter, 100 ml.of ethanol-water (1:1) is added and the solid filtered and washed withethanol-water (1:1) and with water to give tan crystals, m.p. 98°-107°C. Recrystallization from ethanol gives light tan crystals, m.p.114°-116° C.

EXAMPLE 45 Preparation of p-{{3-[p-(Benzyloxyphenyl]propyl}amino}benzoicAcid

A mixture of 8.0 g. of ethylp-{{3-[p-(benzyloxy)phenyl]propyl}amino}benozoate (prepared as describedin Example 44), 8 g. of KOH and 100 ml. of ethanol-water (9:1) isrefluxed for 3.5 hours. The mixture is acidified while hot withconcentrated hydrochloric acid, diluted with water, cooled, filtered andthe solid washed with water to give tan crystals, m.p. 170°-172° C.Recrystallization from ethanol gives off-white crystals, m.p. 171°-172°C.

EXAMPLE 46 Preparation of 6-Phenylhexanol

To 100 ml. of 1 molar borane in tetrahydrofuran cooled in an ice bath isadded 19.2 g. of 6-phenylhexanoic acid over a period of 30 minutes. Thesolution is stirred for 1.5 hours and an additional 100 ml. of 1 molarborane in tetrahydrofuran is added. After stirring overnight at roomtemperature the reaction mixture is poured into 500 g. of ice. Themixture is extracted with ether, the extracts washed with water, driedover magnesium sulfate and concentrated under reduced pressure to give6-phenylhexanol as a light yellow liquid.

EXAMPLE 47 Preparation of 6-Phenylhexanol O-Methanesulfonate

To a chilled (-4° C.) solution of 19.4 g. of 6-phenylhexanol (preparedas described in Example 46) and 15.1 g. of triethylamine in 500 ml. ofdichloromethane is added dropwise, over 5 minutes, 12.6 g. ofmethanesulfonyl chloride. The mixture is stirred at -10° C. for 30minutes and the solution washed successively with 200 ml. of cold water,200 ml. of cold 10% hydrochloric acid, 200 ml. of cold saturated sodiumbicarbonate and 200 ml. of cold saturated sodium chloride solution. Theorganic layer is dried over magnesium sulfate and the solvent removedunder reduced pressure to give 6-phenylhexanol O-methanesulfonate as anoil.

EXAMPLE 48 Preparation of Ethyl 4-[6-(phenylhexyl)amino]benzoate

A solution of 34.9 g. of ethyl p-aminobenzoate, 26.9 g. of6-phenylhexanol O-methanesulfonate (prepared as described in Example 47)and 200 ml. of hexamethylphosphoramide is heated at 110° C. in an oilbath for 20 hours. The mixture is cooled, diluted with 100 ml. of waterand filtered. The solid is washed with 60 ml. of ethanol-water (1:1) togive crude ethyl 4-(6-phenylhexylamino)benzoate. Purification gives theproduct as crystals, m.p. 69.5°-72.5° C.

EXAMPLE 49 Preparation of 2-(2-Thienyl)ethanol O-Methanesulfonate

A mixture of 12.8 g. of 2-(2-thienyl)ethanol, 450 ml. of dichloromethaneand 20.2 g. of triethylamine is chilled to -10° C. and 12.8 g. of coldmethanesulfonyl chloride is added dropwise over 30 minutes. Afterstirring for 1 hour, the mixture is washed with 300 ml. of cold water,300 ml. of cold 10% hydrochloric acid, 300 ml. of cold saturated sodiumbicarbonate, and 300 ml. of cold saturated sodium chloride solution. Theorganic layer is dried over magnesium sulfate and concentrated undervacuum to give the product as an oil.

EXAMPLE 50 Preparation of Ethyl 4-[2-(2-thienyl)ethylamino]benzoate

A mixture of 33.0 g. of ethyl p-aminobenzoate, 21.8 g. of2-(2-thienyl)ethanol O-methanesulfonate (prepared as described inExample 49) and 100 ml. of hexamethylphosphoramide is heated in an oilbath at 125° C. for 16 hours. The mixture is chilled, diluted with 15ml. of ethanol and 150 ml. of water. The mixture is extracted with etherand the ether extracts washed with water, dried over magnesium sulfateand concentrated in vacuo to give a crude oil. A sample of this oil ischromatographed over silica gel and the fractions containing the productare combined and recrystallized from hexane to give ethyl4-[2-(2-thienyl)ethylamino]benzoate as yellow-tan crystals, m.p. 93°-95°C.

EXAMPLE 51 Preparation of 4-[2-(2-Thienyl)ethylamino]benzoic Acid

A mixture of 29.7 g. of crude ethyl 4-[2-(2-thienyl)ethylamino]benzoate,29 g. of potassium hydroxide and 200 ml. of 95% ethanol is refluxed for3 hours. The solution is diluted with 100 ml. of water and adjusted topH 6 with concentrated hydrochloric acid. The mixture is cooled,filtered and the solid washed with ethanol-water (1:1) to give a solid.The solid is heated with 200 ml. of ethanol, filtered and the filtrateconcentrated. Purification gives the product, m.p. 163°-165° C.

EXAMPLE 52 Preparation of p-Heptyloxybenzyl alcohol

To a solution of 125 ml. of 1 molar borane in tetrahydrofuran chilled inan ice bath is added 19.3 g. of p-heptyloxybenzoic acid in 160 ml. oftetrahydrofuran over a period of 45 minutes. The mixture is stirred atroom temperature for 5.5 hours, poured into ice and water and 30 ml. ofconcentrated hydrochloric acid added. The mixture is filtered and thesolid washed with water to give the product as a white waxy solid.

EXAMPLE 53 Preparation of p-Heptyloxybenzyl alcohol O-Methanesulfonate

A mixture of 17.7 g. of p-heptyloxybenzyl alcohol (prepared as describedin Example 52), 16.7 ml. of triethylamine and 380 ml. of drydichloromethane is chilled at -9° C. and 6.81 ml. of methanesulfonylchloride is added dropwise over 5 minutes. The mixture is stirred at -9°C. for 30 minutes and the solution washed successively with 250 ml. ofcold water, 200 ml. of cold water, 200 ml. of cold 10% hydrochloricacid, 250 ml. of cold saturated sodium bicarbonate and 200 ml. of coldsodium chloride solution. The organic layer is dried over magnesiumsulfate and the solvent removed under reduced pressure to give theproduct as a yellow oil.

EXAMPLE 54 Preparation of Ethyl p-{[p-(heptyloxy)benzyl]amino}benzoate

A mixture of 13.5 g. of p-(heptyloxy)benzyl alcohol O-methanesulfonate(prepared as described in Example 53), 14.9 g. of ethyl p-aminobenzoateand 50 ml. of hexamethylphosphoramide is heated at 120° C. for 24 hours.The mixture is cooled, diluted with 40 ml. of ethanol-water (1:1) andchilled. Filtration gives a crude product which is recrystallized from95% ethanol and from ethanol to give white crystals, m.p. 111°-113° C.

EXAMPLE 55 Preparation of p-{[p-(Heptyloxy)benzyl]amino}benzoic Acid

A mixture of 5 g. of ethyl p-[p-(heptyloxy)benzyl]amino benzoate(prepared as described in Example 54), 1.51 g. of potassium hydroxideand 50 ml. of 95% ethanol is refluxed for 5 hours. Concentratedhydrochloric acid is added and the mixture diluted with 150 ml. ofwater. Chilling and filtering gives crystals which are recrystallizedfrom ethanol to give white crystals, m.p. 148°-152.5° C.

EXAMPLE 56 Preparation of p-Decylbenzyl alcohol

To 69.5 ml. of 1 molar borane in tetrahydrofuran chilled in an ice bathis added dropwise over 40 minutes a solution of 17.2 g. ofp-decylbenzoic acid in 150 ml. of dry tetrahydrofuran. The mixture isrefluxed for 3.5 hours, chilled, 5 ml. of concentrated hydrochloric acidis added and the mixture poured onto ice. The mixture is filtered andthe solid washed with water to give white crystals.

EXAMPLE 57 Preparation of p-Decylbenzyl alcohol O-Methanesulfonate

A solution of 17.0 g. of p-decylbenzyl alcohol (prepared as described inExample 56) and 14.3 ml. of triethylamine in 330 ml. of drydichloromethane is chilled to -5° C. to -9° C. and 5.85 ml. ofmethanesulfonyl chloride added dropwise with stirring over 7 minutes.The mixture is stirred at -10° C. for 30 minutes and then washedsuccessively with 250 ml. of cold water, 200 ml. of cold 10%hydrochloric acid, 200 ml. of cold saturated sodium bicarbonate and 200ml. of cold saturated sodium chloride solution. The extract is driedover magnesium sulfate and the solvent removed under reduced pressure togive a pale yellow oil which solidifies on standing.

EXAMPLE 58 Preparation of Ethyl p-{[(p-decyl)benzyl]amino}benzoate

A mixture of 20.7 g. of p-decylbenzyl alcohol O-methanesulfonate(prepared as described in Example 57) and 20.5 g. of ethylp-aminobenzoate in 65 ml. of hexamethylphosphoramide is heated at115°-124° C. in an oil bath for 24 hours. The mixture is cooled anddiluted with 60 ml. of ethanol-water (1:1), chilled and filtered to givecream colored crystals, m.p. 87°-90° C.

EXAMPLE 59 Preparation of p-{[(p-Decyl)benzyl]amino}benzoic Acid

A mixture of 10 g. of ethyl p-{[(p-decyl)benzyl]amino}benzoate (preparedas described in Example 58) and 2.84 g. of potassium hydroxide in 90 ml.of 95% ethanol is refluxed for 5 hours. Concentrated hydrochloric acidis added and the mixture diluted with 100 ml. of water. Filtration givescrystals which are washed with water to give a crude product.Recrystallization from ethanol gives white crystals, m.p. 135°-136° C.

EXAMPLE 60 Preparation of Ethyl 4-[2-(α-naphthyl)ethylamino]benzoate

A solution of 4.7 g. of 2-(α-naphthyl)ethyl bromide and 6.6 g. of ethylp-aminobenzoate in 50 ml. of hexamethylphosphoramide is stirred andheated at 110° C. for 16 hours. The mixture is cooled, diluted with 50ml. of water and filtered to give a crude product, which isrecrystallized from ethanol. Recrystallization gives ethyl4-[2-(α-naphthyl)ethylamino]benzoate as white crystals, m.p. 104°-106°C.

EXAMPLE 61 3-(p-Chlorophenyl)propanol O-Mesylate

A solution of 27.6 g. of 3-(p-chlorophenyl)propionic acid in 50 ml. ofdry tetrahydrofuran is added dropwise to 180 ml. of 1 molar borane intetrahydrofuran chilled in an ice bath. After the addition the mixtureis stirred overnight at room temperature and poured into 1 liter of iceand water. The mixture is extracted with ether and the ether extractconcentrated to give 27 g. of product. This product is dissolved in 600ml. of dichloromethane and 30.3 g. of triethylamine added. To thechilled solution (-8° C.) is added dropwise 19.0 g. of methanesulfonylchloride over 1 hour. After stirring 30 minutes the solution is washedwith 400 ml. of each of the following cold solutions; 10% hydrochloricacid, saturated sodium bicarbonate and saturated sodium chloride. Theorganic layer is dried over magnesium sulfate and concentrated to give35 g. of 3-(p-chlorophenyl)propanol O-mesylate.

EXAMPLE 62

Ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate

A solution of 49.5 g. of ethyl 4-aminobenzoate, 34.9 g. of3-(p-chlorophenyl)propanol O-mesylate in 100 ml. ofhexamethylphosphoramide is heated at 125°-130° C. for 16 hours. Thesolution is diluted with 50 ml. of tetrahydrofuran and with 150 ml. ofwater. Chilling and filtering gives crystals which are washed with waterand recrystallized from ethanol to give 28.3 g. of light yellowcrystals. Recrystallizations give the product as crystals, m.p.122°-124° C.

EXAMPLE 63 4-[3-(p-Chlorophenyl)propylamino]benzoic acid

A mixture of 16.3 g. of ethyl 4-[3-(p-chlorophenyl)propylamino]benzoate,16.3 g. of potassium hydroxide and 200 ml. of 95% ethanol is refluxedfor 3 hours. The mixture is diluted with 100 ml. of water brought to pH6 with concentrated hydrochloric acid. Chilling and filtering gave 15 g.of white crystals. Recrystallization from ethanol gave 8.6 g. of whitecrystals, m.p. 191°-192° C.

The compounds of the present invention show hypolipidemic activity inmammals, specifically warm-blooded animals. The mechanism of action ofthese compounds is not known and the inventors do not wish to be limitedto any particular mechanism. However, the compounds of the presentinvention were shown to possess hypolipidemic activity as determined byanimal experiments as follows: The compounds were administered orallyadmixed with the diet to groups of 4-6 male rats, CFE strain fromCarworth Farms. A control group of 6-8 rats was maintained on the dietalone; test groups were maintained on the diet plus the indicatedpercentage of compound by weight. After 6 days treatment serum sterolconcentrations were determined either (1) according to thesaponification and extraction method of P. Trinder, Analyst 77, 321(1952) and the colorimetric determination of Zlatkis, et. al., J. Lab.Clin. Med. 44, 486 (1953) or (2) by the extraction method of H. H.Leffler, Amer. J. Clin. Path. 31, 310 (1959), the overall methodappropriately modified for use with an automatic mechanical analyzer.Serum triglycerides were estimated by the automated procedure of Kesslerand Lederer ["Automation in Analytical Chemistry", Skeggs, L. T., (Ed.),Mediad, Inc., New York, 1965, p. 341]. In these tests a compound isconsidered to have hypolipidemic activity if it depresses serum sterollevels 15% or more below that of the controls, and/or depressestriglyceride levels by 25% or more below controls. Table I showsrepresentative compounds of the present invention and the degree towhich they depress serum sterols and triglyceride levels after a oneweek dosing period.

                                      TABLE I                                     __________________________________________________________________________                           % Compound                                                                           Lowering of Serum                               Compound               in Diet                                                                              Sterol                                                                            Triglyceride                                __________________________________________________________________________    p-(Phenethylamino(benzoic acid                                                                       0.1    12  51                                          p-{[p-(Decyloxy)benzyl]amino}benzoic acid                                                            0.1    18  63                                          p-[(4-Biphenylylmethyl)amino]benzoic acid                                                            0.1    10  61                                          Ethyl p-[(4-biphenylylmethyl)amino]benzoate                                                          0.1     6  52                                          p-[(11-Phenylundecyl)amino]benzoic acid                                                              0.1    16  26                                                                 0.05   22  31                                          p-Benzylaminobenzoic acid                                                                            0.1    13  35                                          p-[6-(Phenylhexyl)amino]benzoic acid                                                                 0.1    16, 15.sup.1                                                                      60, 52.sup.1                                Ethyl p-[(p-methoxybenzyl)amino]benzoate                                                             0.1    16  52                                          p-[(p-Tridecyloxybenzyl)amino]benzoic acid                                                           0.1    10  49                                          p-(Cinnamylamino)benzoic acid                                                                        0.1    15  52                                                                 0.05   29  51                                          p-[(3-Phenylpropyl)amino]benzoic acid                                                                0.1    19  37                                                                 0.05   26  49                                          trans-Ethyl-p-[(cinnamyl)amino]benzoate                                                              0.1    15  40                                          Ethyl p-[(3-phenylpropyl)amino]benzoate                                                              0.1    21  43                                          Ethyl p-[(10-phenyldecyl)amino]benzoate                                                              0.1    11  23                                                                 0.05   15  42                                          Ethyl p-[(5-phenylpentyl)amino]benzoate                                                              0.1    10  38                                                                 0.05   15  34                                          p-[4-(2-Thienylbutyl)amino]benzoic acid                                                              0.1    23  10                                          p-[(p-Fluorophenethyl)amino]benzoic acid                                                             0.1    11  46                                          Ethyl 4-[6-(phenylhexyl)amino]benzoate                                                               0.1    19  57                                                                 0.05   17  55                                          Ethyl 4-[2-(2-thienyl)ethylamino]benzoate                                                            0.1    15  31                                          p-{[p-(Heptyloxy)benzyl]amino}benzoic acid                                                           0.1    17  28                                                                 0.05   17  30                                          Ethyl p-{{3-[p-(benzyloxy)phenyl] propyl}-                                                           0.1     4  45                                          amino}benzoate         0.05   14  54                                          __________________________________________________________________________     .sup.1 The results 15 and 52 were obtained from a 4 week study.          

The compounds of the present invention are useful as hypolipidemicagents in mammals when administered in amounts ranging from about 0.5mg. per kg. to about 40 mg. per kg. of body weight per day. A preferreddosage regimen for optimum results would be from about 2 mg. per kg. toabout 29 mg. per kg. of body weight per day. Thus the daily dosageemployed for a subject of about 70 kg. of about 35 mg. to about 2.8 g.and preferably about 140 mg. to about 2.0 g.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an assimilableedible carrier, or they may be enclosed in hard or soft gelatincapsules, or they may be compressed into tablets, or they may beincorporated directly with the food of the diet. For oral therapeuticadministration, the active compounds of this invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum or the like.Such compositions and preparations should contain at least 0.1% ofactive compound. The percentage in the compositions and preparationsmay, of course, be varied and may conveniently be between about 5% and75% or more of the weight of the unit. The amount of active compound insuch therapeutically useful compositions or preparations is such that asuitable dosage will be obtained. Preferred compositions or preparationsare prepared so that an oral dosage unit form contains between about 10mg. and 500 mg. of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: a binder such as gum tragacanth, acacia, corn starch orgelatin; an excipient such as dicalcium phosphate; a disintegratingagent such as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring. When thedosage unit form is a capsule, it may contain in addition to materialsof the above type a liquid carrier such as a fatty oil. Various othermaterials may be present as coatings or to otherwise modify the physicalform of the dosage unit. For instance, tablets, pills or capsules may becoated with shellac, sugar or both. A syrup or elixir may contain theactive compounds, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry ororange flavor. Any material used in preparing any dosage unit formshould be pharmaceutically pure and substantially non-toxic in theamounts employed. In addition, the active ingredients may beincorporated into sustained release preparations.

We claim:
 1. A compound of the formula: ##STR4## wherein n is an integerfrom 3 to 16, R₁ is hydrogen, lower alkyl, benzyl, di(loweralkyl)aminoethyl or lower alkoxyethyl, and R₂ is phenyl, 4-halophenyl,2,4-dihalophenyl, 2,4,6-trihalophenyl, 4-(lower alkoxy)phenyl,2,4-di(lower alkoxy)phenyl, 2,4,6-tri(lower alkoxy)phenyl,4-benzyloxyphenyl, 4-(lower alkyl)phenyl, 2,4-di(lower alkyl)phenyl,2,4,6-tri(lower alkyl)phenyl, 1-naphthyl, 2-naphthyl or biphenyl; thepharmaceutically acceptable salts thereof and the alkali metal ororganic base carboxylic acid salts thereof when R₁ is hydrogen.
 2. Thecompound according to claim 1, p-(cinnamylamino)benzoic acid.
 3. Thecompound according to claim 1, ethyl p-(cinnamylamino)benzoate.
 4. Amethod of lowering serum lipid levels in mammals which comprisesadministering internally to said mammals a hypolipidemically effectiveamount of a compound of claim
 1. 5. A method of lowering serum lipidlevels in mammals which comprises administering internally to saidmammals a hypolipidemically effective amount of a compound of theformula: ##STR5## wherein n is an integer from 1 to 16, R₁ is hydrogen,lower alkyl, benzyl, di(lower alkyl)aminoethyl or lower alkoxyethyl, andR₂ is phenyl, 4-halophenyl, 2,4-dihalophenyl, 2,4,6-trihalophenyl,4-(lower alkoxy)phenyl, 2,4-di(lower alkoxy)phenyl, 2,4,6-tri(loweralkoxy)phenyl, 4-benzyloxyphenyl, 4-(lower alkyl)phenyl, 2,4-di(loweralkyl)phenyl, 2,4,6-tri(lower alkyl)phenyl, 1-naphthyl, 2-naphthyl orbiphenyl; the pharmaceutically acceptable salts thereof and the alkalimetal or organic base carboxylic acid salts thereof when R₁ is hydrogen.6. The method according to claim 5 wherein the compound isp-[(11-phenylundecyl)amino]benzoic acid.
 7. The method according toclaim 5 wherein the compound is p-[(6-phenylhexyl)amino]benzoic acid. 8.The method according to claim 5 wherein the compound is ethyl4-[(6-phenylhexyl)amino]benzoate.
 9. The method according to claim 5wherein the compound is ethyl p-[(3-phenylpropyl)amino]benzoate.
 10. Themethod according to claim 5 wherein the compound isp-[(3-phenylpropyl)amino]benzoate acid.
 11. The method according toclaim 5 wherein said compound is administered to provide a daily dosageof from about 0.5 mg. to about 40 mg. per kg. of body weight of saidmammal.
 12. The method according to claim 5 wherein said daily dosage isabout 2 mg. to about 20 mg. per kg. of body weight of said mammal.